REGULATION OF PROTEOGLYCAN EXPRESSION IN FIBROTIC LIVER AND CULTURED FAT-STORING CELLS

Considerable progress has been made in recent years with the molecular dissection of proteoglycans in normal and fibrotic human and rat live r. Proteoglycans constitute a major fraction of extracellular, pericel lular and intracellular glycoconjugates. In former times, proteoglycan s were classified nearly exclusively on the basis of the composition o f their carbohydrate chain (glycosaminoglycan, GAG) attached to the co re protein. Accordingly, three main types are discerned in liver, whic h are in order of decreasing concentrations heparan sulfate (HS, more than 60% of total GAG), dermatan sulfate and chondroitin-4,6-sulfate i somers. Keratan sulfate has not been detected in rat and human liver. Recently, proteoglycans have been characterized by sequencing and clon ing of the core proteins to which a number of specific glycosaminoglyc an side chains are covalently linked. Accordingly, decorin and biglyca n have been identified as major chondroitin sulfate/dermatan sulfate p roteoglycans in the extracellular space. In addition, evidence was obt ained recently for the expression of aggrecan and lumican, both Kerata n sulfate bearing proteoglycans, and of syndecan in liver. Using in si tu hybridization techniques the temporal and spatial pattern of expres sion of biglycan, decorin and aggrecan has been assessed. These studie together with Northern blot hybridizations performed with isolated pa renchymal and nonparenchymal liver cells confirm that felt-storing cel ls (Ito cells, perisinusoidal lipocytes), are the most important, prin cipal cellular site of proteoglycan production in diseased liver. The level of expression is regulated by a number of cytokines among which TGF beta, TNF alpha and TGF alpha play significant roles. The effects of these cytokines on proteoglycan expression are dependent on the sta ge of phenotypic transition of fat storing cells to the activated myof ibroblast. Taken together, these data point to the potentially signifi cant role which proteoglycans might fulfil in the regulation of cellul ar functions and in the maintenance of the supramolecular organization of the extracellular matrix in normal and In diseased liver during th e process of fibrogenesis.